More Effective Distributed ML via a Stale Synchronous Parallel Parameter Server.
We propose a parameter server system for distributed ML, which follows a Stale Synchronous Parallel (SSP) model of computation that maximizes the time computational workers spend doing useful work on ML algorithms, while still providing correctness guarantees. The parameter server provides an easy-to-use shared interface for read/write access to an ML model's values (parameters and variables), and the SSP model allows distributed workers to read older, stale versions of these values from a local cache, instead of waiting to get them from a central storage. This significantly increases the proportion of time workers spend computing, as opposed to waiting. Furthermore, the SSP model ensures ML algorithm correctness by limiting the maximum age of the stale values. We provide a proof of correctness under SSP, as well as empirical results demonstrating that the SSP model achieves faster algorithm convergence on several different ML problems, compared to fully-synchronous and asynchronous schemes.


Neuropeptide Y preferentially potentiates responses to adrenergic nerve stimulation by increasing rate of contraction.
Neuropeptide Y (NPY) is colocalized with norepinephrine and coreleased from adrenergic nerves. NPY reportedly can influence vascular neuroeffector transmission in both negative and positive directions. Mechanisms by which NPY effects are exerted and their relative contribution may vary between different blood vessels. Therefore, we investigated effects of NPY on adrenergic neurotransmission in ring segments of the rat tail artery by measuring isometric force development and [3H]norepinephrine release. NPY (1-100 nM) potentiated responses to transmural nerve stimulation (3 Hz, six pulses) by more than 300% but produced no direct contractile effects. NPY potentiated responses to longer transmural nerve stimulation trains (30-100 pulses) or to exogenous norepinephrine by only 30%. NPY had no effect on [3H]norepinephrine overflow with either short (six pulses) or long (30 pulses) stimulation trains. Contractile responses to transmural nerve stimulation were completely blocked by prazosin (10(-7) M) both in the absence and presence of NPY. Since the impact of an increased rate of contraction on the contractile response achieved would be greater with short stimulation trains, the effect of NPY on contraction rate was analyzed. NPY increased the rate of contraction to both norepinephrine and transmural nerve stimulation. It is hypothesized that NPY increases the early (phasic) component of the contractile response by preferentially influencing release of intracellular calcium stores. These findings suggest that the effects of NPY will be more profound on phasic rather than sustained patterns of nerve traffic.


Cost and resource use of patients on antiretroviral therapy in the urban and semiurban public sectors of South Africa.
South Africa has the world's largest number of patients on antiretroviral treatment (ART). As coverage expands beyond urban environments, the cost of care is becoming increasingly important. Health care cost data for the first year after initiation were analyzed for cohorts of patients in a semiurban and an urban public sector ART clinic in South Africa. We compared mean cost by CD4 cell count and time on ART between clinics. Patients in both clinics had comparable CD4 cell counts at initiation and under treatment. In the urban clinic, mean cost per patient-year on ART in 2011 USD was $1040 [95% confidence interval (CI): $800 to $1280], of which outpatient cost was $692 (67%) and inpatient cost was $348 (33%). Fourteen percent of urban patients required inpatient care at a mean length of stay of 9 days and mean cost per hospitalized patient of $1663 (95% CI: $1103 to $2041). In the semiurban clinic, mean cost per patient-year on ART was $1115 (95% CI: $776 to $1453), of which outpatient cost was $697 (63%) and inpatient cost $418 (37%). Seven percent of semiurban patients required inpatient care at a mean length of stay of 28 days and mean cost per hospitalized patient of $3824 (95% CI: $1143 to $6505). Outpatient ART provision in the semiurban setting cost the same as in the urban setting, but inpatient costs are higher in the semiurban clinic because of longer hospitalizations. Cost in both clinics was highest in the first 3 months on ART and at CD4 cell counts <50 cells/μL.


Liquid-crystal polarization rotator and a tunable polarizer.
A liquid-crystal (LC) voltage-controlled linear polarizer is demonstrated using two LC retarders stacked with two quarter-wave plates and an intermediate linear absorptive polarizer. The device was examined experimentally using unpolarized light and was found to be in accordance with the theoretical prediction. Under certain conditions the device acts as a polarization rotator with possibility for simultaneous amplitude modulation. Hence it has a potential application in high-dynamic-range polarimetric imaging.


Risk of Cerebrovascular Diseases After Uvulopalatopharyngoplasty in Patients With Obstructive Sleep Apnea: A Nationwide Cohort Study.
Little was known about the beneficial effects of uvulopalatopharyngoplasty (UPPP) on the outcomes after obstructive sleep apnea (OSA). The aim of this study is to investigate the effects of UPPP on reducing risk of cerebrovascular diseases in patients with OSA.Using Taiwan's National Health Insurance Research Database, we conducted a retrospective cohort study of 10,339 patients with new OSA between January 1, 2004, and December 31, 2009. The incident cerebrovascular disease was identified during the 1-year follow-up period in patients with and without receiving UPPP. The rate ratios (RRs) and 95% confidence intervals (CIs) of cerebrovascular disease associated with receiving UPPP in patients with OSA were calculated in multivariate Poisson regression.The 1-year incidences of cerebrovascular disease for OSA patients with and without UPPP were 1.06% and 5.14%, respectively. Patients with OSA receiving UPPP had lower risk of cerebrovascular disease compared with those without UPPP (RR, 0.45; 95% CI, 0.33-0.61). The decreased risk of cerebrovascular disease following UPPP was observed in both sexes and all age groups. In the stratified analysis of medical conditions, the RR of cerebrovascular disease associated with UPPP for patients with 0, 1, ≥ 2 medical conditions were 0.28 (95% CI 0.12-0.68), 0.39 (95% CI 0.21-0.73), and 0.63 (95% CI 0.43-0.93), respectively.Patients with OSA who received UPPP had lower risk of cerebrovascular disease within 1 year after surgery compared with patients not receiving UPPP. Clinical physicians could have more evidence to persuade patients to receive surgical intervention, especially those who have severe OSA symptoms or do not acquire adequate symptom relief under conservative treatments.


Blood levels of immune cells predict survival in myeloma patients: results of an Eastern Cooperative Oncology Group phase 3 trial for newly diagnosed multiple myeloma patients.
Previously, it was reported that patients with multiple myeloma (MM) who have higher baseline levels of blood CD4(+) or CD19(+) cells have longer survival. This article extends the analysis of immune cell levels and survival in a large cohort (N = 504) of patients with MM entered on Eastern Cooperative Oncology Group (ECOG) phase 3 trial (9486). Newly diagnosed patients with MM received 2 cycles of vincristine, bischloroethylnitrosourea, melphalan, cytoxan, prednisone (VBMCP) and were treated on one of 3 randomized arms: VBMCP with either interferon or high-dose cyclophosphamide, or VBMCP alone. Blood immune cell levels were studied at trial entry (baseline), after 2 cycles of chemotherapy, after 2 years of therapy, and at relapse. Baseline CD3(+), CD4(+), CD8(+), CD19(+), and CD4(+) subset cell levels were all positively associated with survival (P =.0087 to P <.0001). A multivariate analysis incorporating CD4(+) and CD19(+) cell levels defined 3 separate groups of patients with MM to survival outcome. Higher CD19(+) blood levels were positively associated with MM-patient survival at entry to the study, at year 2, and at relapse (P <.0001 at all 3 timepoints). Patients with MM had evidence of immune cell reconstitution after 2 years of therapy, but the rate and extent of recovery was greater for CD8(+), which was greater than CD4(+), which was greater than CD19(+). This latter data affirms the positive relationship between the quantitative status of the blood immune system in MM and survival. In addition, the importance of the CD19(+) blood cells to survival is evident throughout the course of MM. Therapeutic efforts to maintain an intact immune system may be crucial in maximizing chemotherapeutic and/or immunotherapy efforts in this disease.


ClonalFrameML: efficient inference of recombination in whole bacterial genomes.
Recombination is an important evolutionary force in bacteria, but it remains challenging to reconstruct the imports that occurred in the ancestry of a genomic sample. Here we present ClonalFrameML, which uses maximum likelihood inference to simultaneously detect recombination in bacterial genomes and account for it in phylogenetic reconstruction. ClonalFrameML can analyse hundreds of genomes in a matter of hours, and we demonstrate its usefulness on simulated and real datasets. We find evidence for recombination hotspots associated with mobile elements in Clostridium difficile ST6 and a previously undescribed 310kb chromosomal replacement in Staphylococcus aureus ST582. ClonalFrameML is freely available at http://clonalframeml.googlecode.com/.


Metal artifact reduction in patients with dental implants using multispectral three-dimensional data acquisition for hybrid PET/MRI.
Hybrid positron emission tomography/magnetic resonance imaging (PET/MRI) shows high potential for patients with oropharyngeal cancer. Dental implants can cause substantial artifacts in the oral cavity impairing diagnostic accuracy. Therefore, we evaluated new MRI sequences with multi-acquisition variable-resonance image combination (MAVRIC SL) in comparison to conventional high-bandwidth techniques and in a second step showed the effect of artifact size on MRI-based attenuation correction (AC) with a simulation study. Twenty-five patients with dental implants prospectively underwent a trimodality PET/CT/MRI examination after informed consent was obtained under the approval of the local ethics committee. A conventional 3D gradient-echo sequence (LAVA-Flex) commonly used for MRI-based AC of PET (acquisition time of 14 s), a T1w fast spin-echo sequence with high bandwidth (acquisition time of 3.2 min), as well as MAVRIC SL sequence without and with increased phase acceleration (MAVRIC, acquisition time of 6 min; MAVRIC-fast, acquisition time of 3.5 min) were applied. The absolute and relative reduction of the signal void artifact was calculated for each implant and tested for statistical significance using the Wilcoxon signed-rank test. The effect of artifact size on PET AC was simulated in one case with a large tumor in the oral cavity. The relative difference of the maximum standardized uptake value (SUVmax) in the tumor was calculated for increasing artifact sizes centered over the second molar. The absolute reduction of signal void from LAVA-Flex sequences to the T1-weighted fast spin-echo (FSE) sequences was 416 mm(2) (range 4 to 2,010 mm(2)) to MAVRIC 481 mm(2) (range 12 to 2,288 mm(2)) and to MAVRIC-fast 486 mm(2) (range 39 to 2,209 mm(2)). The relative reduction in signal void was significantly improved for both MAVRIC and MAVRIC-fast compared to T1 FSE (-75%/-78% vs. -62%, p < 0.001 for both). The relative error for SUVmax was negligible for artifacts of 0.5-cm diameter (-0.1%), but substantial for artifacts of 5.2-cm diameter (-33%). MAVRIC-fast could become useful for artifact reduction in PET/MR for patients with dental implants. This might improve diagnostic accuracy especially for patients with tumors in the oropharynx and substantially improve accuracy of PET quantification.


Prevalence and factors associated with multimorbidity among primary care patients with decreased renal function.
To establish the prevalence of multimorbidity in people with chronic kidney disease (CKD) stages 1-5 and transiently impaired renal function and identify factors associated with multimorbidity. Prospective cohort study in UK primary care. 861 participants aged 60 and older with decreased renal function of whom, 584 (65.8%) had CKD and 277 (32.2%) did not have CKD. Participants underwent medical history and clinical assessment, and blood and urine sampling. Multimorbidity was defined as presence of ≥2 chronic conditions including CKD. Prevalence of each condition, co-existing conditions and multimorbidity were described and logistic regression was used to identify predictors of multimorbidity. The mean (±SD) age of participants was 74±7 years, 54% were women and 98% were white. After CKD, the next most prevalent condition was hypertension (n = 511, 59.3%), followed by obesity (n = 265, 30.8%) ischemic heart disease (n = 145, 16.8%) and diabetes (n = 133, 15.4%). Having two co-existing conditions was most common (27%), the most common combination of which was hypertension and obesity (29%). One or three conditions was the next most prevalent combination (20% and 21% respectively). The prevalence of multimorbidity was 73.9% (95%CI 70.9-76.8) in all participants and 86.6% (95%CI 83.9-89.3) in those with any-stage CKD. Logistic regression found a significant association between increasing age (OR 1.07, 95%CI 1.04-0.10), increasing BMI (OR 1.15, 95%CI 1.10-1.20) and decreasing eGFR (OR 0.99, 95%CI 0.98-1.00) with multimorbidity. This analysis is the first to provide an accurate estimate of the prevalence of multimorbidity in a screened older primary care population living with or at risk of CKD across all stages. Hypertension and obesity were the most common combination of conditions other than CKD that people were living with, suggesting that there may be multiple reasons for closely monitoring health status in individuals with CKD.


The continuously growing central nervous system of the Nile crocodile (Crocodylus niloticus).
It is a central assumption that larger bodies require larger brains, across species but also possibly within species with continuous growth throughout the lifetime, such as the crocodile. The current study investigates the relationships between body growth (length and mass) and the rates of growth of various subdivisions of the central nervous system (CNS) (brain, spinal cord, eyes) in Nile crocodiles weighing between 90 g and 90 kg. Although the brain appears to grow in two phases in relation to body mass, initially very rapidly then very slowly, it turns out that brain mass increases continuously as a power function of body mass with a small exponent of 0.256, such that a 10-fold increase in body mass is accompanied by a 1.8-fold in brain mass. Eye volume increases slowly with increasing body mass, as a power function of the latter with an exponent of 0.37. The spinal cord, however, grows more rapidly in mass, accompanying body mass raised to an exponent of 0.54, and increasing in length as predicted, with body mass raised to an exponent of 0.32 (close to the predicted 1/3). While supporting the expectation formulated by Jerison that larger bodies require larger brains to operate them, our findings show that: (1) the rate of increase in brain size is very small compared to body growth; and (2) different parts of the CNS grow at different rates accompanying continuous body growth, with a faster increase in spinal cord mass and eye volume, than in brain mass.


Swelling/floating capability and drug release characterizations of gastroretentive drug delivery system based on a combination of hydroxyethyl cellulose and sodium carboxymethyl cellulose.
The aim of this study was to characterize the swelling and floating behaviors of gastroretentive drug delivery system (GRDDS) composed of hydroxyethyl cellulose (HEC) and sodium carboxymethyl cellulose (NaCMC) and to optimize HEC/NaCMC GRDDS to incorporate three model drugs with different solubilities (metformin, ciprofloxacin, and esomeprazole). Various ratios of NaCMC to HEC were formulated, and their swelling and floating behaviors were characterized. Influences of media containing various NaCl concentrations on the swelling and floating behaviors and drug solubility were also characterized. Finally, release profiles of the three model drugs from GRDDS formulation (F1-4) and formulation (F1-1) were examined. Results demonstrated when the GRDDS tablets were tested in simulated gastric solution, the degree of swelling at 6 h was decreased for each formulation that contained NaCMC in comparison to those in de-ionized water (DIW). Of note, floating duration was enhanced when in simulated gastric solution compared to DIW. Further, the hydration of tablets was found to be retarded as the NaCl concentration in the medium increased resulting in smaller gel layers and swelling sizes. Dissolution profiles of the three model drugs in media containing various concentrations of NaCl showed that the addition of NaCl to the media affected the solubility of the drugs, and also their gelling behaviors, resulting in different mechanisms for controlling a drug's release. The release mechanism of the freely water-soluble drug, metformin, was mainly diffusion-controlled, while those of the water-soluble drug, ciprofloxacin, and the slightly water-soluble drug, esomeprazole, were mainly anomalous diffusion. Overall results showed that the developed GRDDS composed of HEC 250HHX and NaCMC of 450 cps possessed proper swelling extents and desired floating periods with sustained-release characteristics.


Soluble endothelial cell-selective adhesion molecule and incident cardiovascular events in a multiethnic population.
Cell adhesion molecules are key regulators of atherosclerotic plaque development, but circulating levels of soluble fragments, such as intercellular adhesion molecule (sICAM-1) and vascular cell adhesion molecule (sVCAM-1), have yielded conflicting associations with atherosclerotic cardiovascular disease (ASCVD). Endothelial cell-selective adhesion molecule (ESAM) is expressed exclusively in platelets and endothelial cells, and soluble ESAM (sESAM) levels have been associated with prevalent subclinical atherosclerosis. We therefore hypothesized that sESAM would be associated with incident ASCVD. sESAM, sICAM-1, and sVCAM-1 were measured in 2,442 participants without CVD in the Dallas Heart Study, a probability-based population sample aged 30-65 years enrolled between 2000 and 2002. ASCVD was defined as first myocardial infarction, stroke, coronary revascularization, or CV death. A total of 162 ASCVD events were analyzed over 10.4 years. Increasing sESAM was associated with ASCVD, independent of risk factors (HR Q4 vs Q1: 2.7, 95% CI 1.6-4.6). Serial adjustment for renal function, sICAM-1, VCAM-1, and prevalent coronary calcium did not attenuate these associations. Continuous ESAM demonstrated similar findings (HR 1.31, 95% CI 1.2-1.4). Addition of sESAM to traditional risk factors improved discrimination and reclassification (delta c-index: P = .009; integrated-discrimination-improvement index P = .001; net reclassification index = 0.42, 95% CI 0.15-0.68). Neither sICAM-1 nor sVCAM-1 was independently associated with ASCVD. sESAM but not sICAM-1 or sVCAM-1 levels are associated with incident ASCVD. Further studies are warranted to investigate the role of sESAM in ASCVD.


Ensheathing glia function as phagocytes in the adult Drosophila brain.
The mammalian brain contains many subtypes of glia that vary in their morphologies, gene expression profiles, and functional roles; however, the functional diversity of glia in the adult Drosophila brain remains poorly defined. Here we define the diversity of glial subtypes that exist in the adult Drosophila brain, show they bear striking similarity to mammalian brain glia, and identify the major phagocytic cell type responsible for engulfing degenerating axons after acute axotomy. We find that neuropil regions contain two different populations of glia: ensheathing glia and astrocytes. Ensheathing glia enwrap major structures in the adult brain, but are not closely associated with synapses. Interestingly, we find these glia uniquely express key components of the glial phagocytic machinery (e.g., the engulfment receptor Draper, and dCed-6), respond morphologically to axon injury, and autonomously require components of the Draper signaling pathway for successful clearance of degenerating axons from the injured brain. Astrocytic glia, in contrast, do not express Draper or dCed-6, fail to respond morphologically to axon injury, and appear to play no role in clearance of degenerating axons from the brain. However, astrocytic glia are closely associated with synaptic regions in neuropil, and express excitatory amino acid transporters, which are presumably required for the clearance of excess neurotransmitters at the synaptic cleft. Together these results argue that ensheathing glia and astrocytes are preprogrammed cell types in the adult Drosophila brain, with ensheathing glia acting as phagocytes after axotomy, and astrocytes potentially modulating synapse formation and signaling.


Minding matter: how not to argue for the causal efficacy of the mental.
The most fundamental issue of the neurosciences is the question of how or whether the mind and the body can interact with each other. It has recently been suggested in several studies that current neuroimaging evidence supports a view where the mind can have a well-documented causal influence on various brain processes. These arguments are critically analyzed here. First, the metaphysical commitments of the current neurosciences are reviewed. According to both the philosophical and neuroscientific received views, mental states are necessarily neurally based. It is argued that this leaves no room for a genuine interaction of the mental and the neural. Second, it is shown how conclusions drawn from recent imaging studies are in fact compatible with the fully physicalistic notion of mental causation and how they can thus be easily accommodated to the received view. The fallacious conclusions are argued to be a result of an overly vague grasping of the conceptual issues involved. The question of whether the fundamental physical principles exclude outright the ability of mental states to have causal influence on the physical world is also addressed and the reaction of appealing to the apparent loophole provided by quantum physics is assessed. It is argued that linking psychology to quantum physics contradicts many basic tenets of the current neurosciences and is thus not a promising line of study. It is concluded that the interactionist hypothesis benefits from neither conceptual nor empirical support.


Preadipocytes proliferate and differentiate under the guidance of Delta-like 1 homolog (DLK1).
Obesity occurs when an excessive dietary fat intake leads to expansion of adipose tissue, which mainly consists of adipocytes that arise from proliferating and differentiating adipose stem cells, the preadipocytes. Obesity is a consequence of both adipocyte hypertrophy and hyperplasia. Knowledge about preadipocyte differentiation is relatively well established, whereas the mechanism responsible for preadipocyte proliferation is incompletely understood and only in the early stage of comprehension. In this regard, we have recently identified that Delta-like 1 homolog (Dlk1) (also known as Preadipocyte factor 1 [Pref-1]) inhibits preadipocyte proliferation by regulating their entry into G1/S-phase. This novel disclosure, adding to the previous published data on Dlk1 repression of preadipocyte differentiation, has given us the chance to firmly place Dlk1 as a master regulator of preadipocyte homeostasis and adipose tissue expansion. Dlk1 manipulation may, therefore, open new perspectives in obesity treatments.


Neighbourhood walkability, road density and socio-economic status in Sydney, Australia.
Planning and transport agencies play a vital role in influencing the design of townscapes, travel modes and travel behaviors, which in turn impact on the walkability of neighbourhoods and residents' physical activity opportunities. Optimising neighbourhood walkability is desirable in built environments, however, the population health benefits of walkability may be offset by increased exposure to traffic related air pollution. This paper describes the spatial distribution of neighbourhood walkability and weighted road density, a marker for traffic related air pollution, in Sydney, Australia. As exposure to air pollution is related to socio-economic status in some cities, this paper also examines the spatial distribution of weighted road density and walkability by socio-economic status (SES). We calculated walkability, weighted road density (as a measure of traffic related air pollution) and SES, using predefined and validated measures, for 5858 Sydney neighbourhoods, representing 3.6 million population. We overlaid tertiles of walkability and weighted road density to define "sweet-spots" (high walkability-low weighted road density), and "sour- spots" (low walkability-high weighted road density) neighbourhoods. We also examined the distribution of walkability and weighted road density by SES quintiles. Walkability and weighted road density showed a clear east-west gradient across the region. Our study found that only 4 % of Sydney's population lived in sweet-spot" neighbourhoods with high walkability and low weighted road density (desirable), and these tended to be located closer to the city centre. A greater proportion of neighbourhoods had health limiting attributes of high weighted road density or low walkability (about 20 % each), and over 5 % of the population lived in "sour-spot" neighbourhoods with low walkability and high weighted road density (least desirable). These neighbourhoods were more distant from the city centre and scattered more widely. There were no linear trends between walkability/weighted road density and neighbourhood SES. Our walkability and weighted road density maps and associated analyses by SES can help identify neighbourhoods with inequalities in health-promoting or health-limiting environments. Planning agencies should seek out opportunities for increased neighbourhood walkability through improved urban development and transport planning, which simultaneously minimizes exposure to traffic related air pollution.


A Comparative Study on Single and Multiple Point Crossovers in a Genetic Algorithm for Coarse Protein Modeling.
The protein structure prediction problem is a holy grail for life science researchers. Computational protein structure prediction involves the folding of protein sequence (string) into the tertiary structure, called the native protein structure. The hydrophobic polar (HP) model is one of the basic models used to investigate the protein folding mechanism at the coarse level. In the HP model, the protein structure prediction problem is defined as an optimization problem, where the protein sequence must be folded over a lattice space such that the protein structure exhibits the lowest value of free energy. However, with the HP model, protein structure prediction is a nondeterministic polynomial (NP)-complete problem and is, therefore, simulated using meta-heuristic algorithms. Simulation of the HP model results in the formation of various protein structures called protein conformations. In this article, we present a case study on the application of a genetic algorithm to simulate the HP model based protein structure prediction. In this work, we employ the two versions of crossover functions (single-point vs. multiple-point crossovers) to generate protein conformations. The conformations were assessed based on the presence of hydrophobic contacts identified in the experimental structure. The sensitivity, specificity, and accuracy of simulation algorithm (genetic algorithm) were compared, and the significance of the parameters was statistically evaluated using the paired t-test. Our results indicate that the multipoint crossover operator enhanced the performance of genetic algorithm compared to genetic algorithm with single-point crossover. Also, multipoint crossover reduced the generation of false conformations, which results in a significant reduction in computational cost.


Alcohol consumption and cigarette smoking increase the frequency of p53 mutations in non-small cell lung cancer.
Epidemiological studies have demonstrated a strong association between tobacco use and lung cancer; however, the genetic targets of these carcinogens and the role of other environmental agents in this process have yet to be defined. We examined the contribution of alcohol use and cigarette smoking top53 gene mutations in patients with non-small cell lung cancer. Mutations of the p53 gene were detected by sequence analysis in 105 patients with non-small cell lung cancer. Patient characteristics significantly associated with p53 gene mutations were determined using logistic regression. Mutations in the p53 gene were present in 53% of the patients (56 of 105). p53 mutations were more common in patients who used alcohol than in patients who consumed less than one drink per day (72 versus 39%; P = 0.003), and were detected more often smokers than nonsmokers (58% versus 10%, P = 0.02). Mutations in the p53 gene were present more often (P = 0.01) in alcohol drinkers who smoked cigarettes [76% (31 of 41)], than in nondrinkers (<1 drink per day) who smoked cigarettes [42% (20 of 48)] or in nondrinkers who did not smoke [14% (1 of 7)]. In conclusion, alcohol consumption and tobacco use are both associated with p53 mutations in non-small cell lung cancer. The link between exposure to both alcohol and tobacco and p53 mutations raises the possibility that alcohol may enhance the mutagenic effects of cigarette smoke in the lung.


RDFIO: extending Semantic MediaWiki for interoperable biomedical data management.
Biological sciences are characterised not only by an increasing amount but also the extreme complexity of its data. This stresses the need for efficient ways of integrating these data in a coherent description of biological systems. In many cases, biological data needs organization before integration. This is not seldom a collaborative effort, and it is thus important that tools for data integration support a collaborative way of working. Wiki systems with support for structured semantic data authoring, such as Semantic MediaWiki, provide a powerful solution for collaborative editing of data combined with machine-readability, so that data can be handled in an automated fashion in any downstream analyses. Semantic MediaWiki lacks a built-in data import function though, which hinders efficient round-tripping of data between interoperable Semantic Web formats such as RDF and the internal wiki format. To solve this deficiency, the RDFIO suite of tools is presented, which supports importing of RDF data into Semantic MediaWiki, with metadata needed to export it again in the same RDF format, or ontology. Additionally, the new functionality enables mash-ups of automated data imports combined with manually created data presentations. The application of the suite of tools is demonstrated by importing drug discovery related data about rare diseases from Orphanet and acid dissociation constants from Wikidata. The RDFIO suite of tools is freely available for download via pharmb.io/project/rdfio . Through a set of biomedical demonstrators, it is demonstrated how the new functionality enables a number of usage scenarios where the interoperability of SMW and the wider Semantic Web is leveraged for biomedical data sets, to create an easy to use and flexible platform for exploring and working with biomedical data.


Increased regulatory T-cell fraction amidst a diminished CD4 compartment explains cellular immune defects in patients with malignant glioma.
Immunosuppression is frequently associated with malignancy and is particularly severe in patients with malignant glioma. Anergy and counterproductive shifts toward T(H)2 cytokine production are long-recognized T-cell defects in these patients whose etiology has remained elusive for >30 years. We show here that absolute counts of both CD4(+) T cells and CD4(+)CD25(+)FOXP3(+)CD45RO(+) T cells (T(regs)) are greatly diminished in patients with malignant glioma, but T(regs) frequently represent an increased fraction of the remaining CD4 compartment. This increased T(reg) fraction, despite reduced counts, correlates with and is sufficient to elicit the characteristic manifestations of impaired patient T-cell responsiveness in vitro. Furthermore, T(reg) removal eradicates T-cell proliferative defects and reverses T(H)2 cytokine shifts, allowing T cells from patients with malignant glioma to function in vitro at levels equivalent to those of normal, healthy controls. Such restored immune function may give license to physiologic antiglioma activity, as in vivo, T(reg) depletion proves permissive for spontaneous tumor rejection in a murine model of established intracranial glioma. These findings dramatically alter our understanding of depressed cellular immune function in patients with malignant glioma and advance a role for T(regs) in facilitating tumor immune evasion in the central nervous system.


Development of an HIV-1 Microbicide Based on Caulobacter crescentus: Blocking Infection by High-Density Display of Virus Entry Inhibitors.
The HIV/AIDS pandemic remains an enormous global health concern. Despite effective prevention options, 2.6 million new infections occur annually, with women in developing countries accounting for more than half of these infections. New prevention strategies that can be used by women are urgently needed. Topical microbicides specific for HIV-1 represent a promising prevention strategy. Conceptually, using harmless bacteria to display peptides or proteins capable of blocking entry provides an inexpensive approach to microbicide development. To avoid the potential pitfalls of engineering commensal bacteria, our strategy is to genetically display infection inhibitors on a non-native bacterium and rely on topical application of stabilized bacteria before potential virus exposure. Due to the high density cell-surface display capabilities and the inherent low toxicity of the bacterium, the S-layer mediated protein display capabilities of the non-pathogenic bacterium Caulobacter crescentus has been exploited for this approach. We have demonstrated that C. crescentus displaying MIP1α or CD4 interfered with the virus entry pathway and provided significant protection from HIV-1 pseudovirus representing clade B in a standard single cycle infection assay. Here we have expanded our C. crescentus based microbicide approach with additional and diverse classes of natural and synthetic inhibitors of the HIV-1 entry pathway. All display constructs provided variable but significant protection from HIV-1 infection; some with protection as high as 70%. Further, we describe protection from infection with additional viral clades. These findings indicate the significant potential for engineering C. crescentus to be an effective and readily adaptable HIV-1 microbicide platform.


Heat shock protein (hsp70) expression and thermal tolerance in sublethally heat-shocked eastern oysters Crassostrea virginica infected with the parasite Perkinsus marinus.
To investigate whether sublethal heat shock protects Perkinsus marinus (Dermo)-infected oysters Crassostrea virginica from lethal heat stress, and the effects of P. marinus infection on sublethal heat shock response, oysters were first experimentally challenged with P. marinus. Then, when infections in oysters progressed to moderate levels (parasite burden = 10(4) to 10(5) cells g(-1) wet tissue weight), oysters were treated with a sublethal heat shock at 40 degrees C for 1 h (heat shock + Dermo challenge). Other treatment groups included heat-shocked, unchallenged (non-P. marinus challenged) oysters and non-heat-shocked, P. marinus-challenged and -unchallenged oysters. Thermal tolerance was compared among these treatments by administering a lethal heat treatment at 44 degrees C for 1 h, 7 d after sublethal heat shock. Sublethal heat shock enhanced survival to lethal heat treatment in both P. marinus-challenged and -unchallenged oysters. Although levels of hsp70 isoforms (hsp69 and hsp72) did not vary significantly by heat shock or infection with P. marinus, responses due to these treatments were apparent when comparing hsp70 levels within infected and uninfected oysters. Infection enhanced expression of hsp69, regardless of whether oysters were heat shocked or not. In uninfected oysters, hsp72 increased due to heat shock 2 and 7 d post heat shock. Overall, this study demonstrates that heat shock can improve survival in oysters, even in oysters infected with P. marinus. Expression of hsp70 varied among isoforms after sublethal and lethal heat shocks and in infected and uninfected oysters. The heat shock response was not negatively affected by P. marinus infection.


Timing-dependent modulation of the posterior parietal cortex-primary motor cortex pathway by sensorimotor training.
Interplay between posterior parietal cortex (PPC) and ipsilateral primary motor cortex (M1) is crucial during execution of movements. The purpose of the study was to determine whether functional PPC-M1 connectivity in humans can be modulated by sensorimotor training. Seventeen participants performed a sensorimotor training task that involved tapping the index finger in synchrony to a rhythmic sequence. To explore differences in training modality, one group (n = 8) learned by visual and the other (n = 9) by auditory stimuli. Transcranial magnetic stimulation (TMS) was used to assess PPC-M1 connectivity before and after training, whereas electroencephalography (EEG) was used to assess PPC-M1 connectivity during training. Facilitation from PPC to M1 was quantified using paired-pulse TMS at conditioning-test intervals of 2, 4, 6, and 8 ms by measuring motor-evoked potentials (MEPs). TMS was applied at baseline and at four time points (0, 30, 60, and 180 min) after training. For EEG, task-related power and coherence were calculated for early and late training phases. The conditioned MEP was facilitated at a 2-ms conditioning-test interval before training. However, facilitation was abolished immediately following training, but returned to baseline at subsequent time points. Regional EEG activity and interregional connectivity between PPC and M1 showed an initial increase during early training followed by a significant decrease in the late phases. The findings indicate that parietal-motor interactions are activated during early sensorimotor training when sensory information has to be integrated into a coherent movement plan. Once the sequence is encoded and movements become automatized, PPC-M1 connectivity returns to baseline.


Comparison between sitagliptin and nateglinide on postprandial lipid levels: The STANDARD study.
To assess the effects of sitagliptin and nateglinide on lipid metabolism. In a parallel group comparative open trial, patients with type 2 diabetes mellitus under treatment at the Japanese Red Cross Medical Center were randomly assigned to receive either sitagliptin (50 mg once daily) or nateglinide (90 mg three times daily before meals). Eligible patients met the following criteria: age ≥ 20 years; hemoglobin A1c (HbA1c) > 6.5% despite diet and exercise; HbA1c between 6.5% and 8.0%; fasting glucose < 7.77 mmol/L; diet and exercise therapy for more than 3 mo; and ability to read and understand the information for written informed consent. Exclusion criteria were contraindications to sitagliptin, contraindications to nateglinide, pregnancy or possible pregnancy, and severe liver/renal failure. Patients who were considered to be unsuitable by the attending physician for other reasons were also excluded. Blood samples were collected at one and three hours after intake of a test meal. The primary outcome measure was the area under the curve (AUC) of apolipoprotein (Apo) B48 at three hours postprandially. Twenty patients were randomly assigned to the sitagliptin group and sixteen patients were randomized to the nateglinide group. All 36 patients took the medication as directed by the physician in both groups, and they all were analyzed. Apart from antidiabetic drugs, there was no difference between the two groups with respect to the frequency of combined use of lipid-lowering, antihypertensive, and/or antiplatelet drugs. The doses of these medications were maintained during 12 wk of treatment. Detailed dietary advice, together with adequate exercise therapy, was given to the patients so that other factors apart from the two test drugs were similar in the two groups. There were no significant differences of the baseline characteristics between the two groups, except for body mass index (the sitagliptin group: 25.14 ± 3.05 kg/m(2); the nateglinide group: 21.39 ± 2.24 kg/m(2)). Fasting levels of HbA1c, glycated albumin, 1.5-anhydroglucitol, and blood glucose, as well as the blood glucose levels at one and three hours postprandially, improved in both groups after 12 wk of treatment, and there were no significant differences between the two groups. However, the glucagon level at one hour postprandially (P = 0.040) and the diastolic blood pressure (P < 0.01) only showed a significant decrease in the sitagliptin group. In the nateglinide group, there was no significant change in the AUC of Apo B48, the glucagon level at one hour postprandially, the fasting triglyceride level, or the diastolic blood pressure. Body weight was unchanged in both groups. However, the AUC of Apo B48 at three hours postprandially showed a significant decrease in the sitagliptin group from 2.48 ± 0.11 at baseline to 1.94 ± 0.78 g/L per hour after 12 wk (P = 0.019). The fasting triglyceride level also decreased significantly in the sitagliptin group (P = 0.035). With regard to lipid-related markers other than Apo B48 and fasting triglycerides, no significant changes were observed with respect to Apo A1, Apo B, or Apo C3 in either group. No adverse events occurred in either group. Sitagliptin significantly improves some lipid parameters while having a comparable effect on blood glucose to nateglinide. A large-scale prospective study of sitagliptin therapy is warranted.


A model for neuronal competition during development.
We report that developmental competition between sympathetic neurons for survival is critically dependent on a sensitization process initiated by target innervation and mediated by a series of feedback loops. Target-derived nerve growth factor (NGF) promoted expression of its own receptor TrkA in mouse and rat neurons and prolonged TrkA-mediated signals. NGF also controlled expression of brain-derived neurotrophic factor and neurotrophin-4, which, through the receptor p75, can kill neighboring neurons with low retrograde NGF-TrkA signaling whereas neurons with high NGF-TrkA signaling are protected. Perturbation of any of these feedback loops disrupts the dynamics of competition. We suggest that three target-initiated events are essential for rapid and robust competition between neurons: sensitization, paracrine apoptotic signaling, and protection from such effects.


IFI16 Expression Is Related to Selected Transcription Factors during B-Cell Differentiation.
The interferon-inducible DNA sensor IFI16 is involved in the modulation of cellular survival, proliferation, and differentiation. In the hematopoietic system, IFI16 is consistently expressed in the CD34+ stem cells and in peripheral blood lymphocytes; however, little is known regarding its regulation during maturation of B- and T-cells. We explored the role of IFI16 in normal B-cell subsets by analysing its expression and relationship with the major transcription factors involved in germinal center (GC) development and plasma-cell (PC) maturation. IFI16 mRNA was differentially expressed in B-cell subsets with significant decrease in IFI16 mRNA in GC and PCs with respect to naïve and memory subsets. IFI16 mRNA expression is inversely correlated with a few master regulators of B-cell differentiation such as BCL6, XBP1, POU2AF1, and BLIMP1. In contrast, IFI16 expression positively correlated with STAT3, REL, SPIB, RELA, RELB, IRF4, STAT5B, and STAT5A. ARACNE algorithm indicated a direct regulation of IFI16 by BCL6, STAT5B, and RELB, whereas the relationship between IFI16 and the other factors is modulated by intermediate factors. In addition, analysis of the CD40 signaling pathway showed that IFI16 gene expression directly correlated with NF-κB activation, indicating that IFI16 could be considered an upstream modulator of NF-κB in human B-cells.


Effects of vasoconstriction and distal dilation on carotid stenoses in the dog.
Traditionally, arterial stenoses have been assumed to be inflexible, static obstructive lesions that could not acutely change their configuration or cross-sectional area. However, recent clinical and experimental observations have shown that coronary arterial stenoses can respond to vasoconstriction and intraluminal pressure changes. This experimental study evaluated whether similar dynamic changes could occur in a carotid artery stenosis. The effects of dilation distal to a circumferential snare were examined in 6 mongrel dogs. To eliminate collateral flow, the distal carotid artery was occluded and blood flow diverted through a 16 or 20 gauge needle. With no stenosis, distal dilation increased flow from 29.0 +/- 2.0 to 90.1 +/- 3.8 ml/min, (p less than 0.01). With moderate stenosis, the flow increase (25.5 +/- 1.3 to 56.4 +/- 3.7 ml/min, p less than 0.01 following dilation was attenuated. With severe stenosis, flow paradoxically decreased (20.4 +/- 1.0 to 11.4 +/- 1.0 ml/min, (p less than 0.01). This flow decrease was associated with a large stenotic resistance increase (2.13 +/- 0.51 to 18.93 +/- 5.58 mm Hg/ml . min-1, (p less than 0.01). In eight additional experiments, an in vitro preparation was used to examine the effects of vasoconstriction on stenotic severity. Vasoconstriction, induced by ergonovine, methoxamine, angiotensin, or vasopressin, resulted in a significant flow decrease and stenotic resistance increase. Thus, both vasoconstriction and intraluminal pressure were shown to affect stenotic severity, and thereby influence blood flow. These data illustrate hemodynamic factors which may be important in patients with severe carotid artery stenosis.


Salivary cortisol response to psychological stress in children with early childhood caries.
Early Childhood Caries (ECC) is a multi-factorial disease and has numerous biological, psychological, and behavioral risk factors. In this study, we have attempted to study psychological stress as a risk factor for early childhood caries by investigating and comparing the response of event-related stress on salivary cortisol level in children with ECC and those without ECC and also compared the adaptability to various dental procedures in children with early childhood caries and without early childhood caries. One hundred children aged between four and five years were examined in the school and 16 pairs of children with caries and without caries were selected after cross-matching them on various risk factors for Early Childhood Caries. Oral prophylaxis and topical fluoride treatment procedures were used as stressors and salivary samples were collected at the time of arrival for the treatment, after Oral Prophylaxis and Fluoride treatment. The salivary samples were analyzed by radioimmunoassay for an unbound plasma cortisol level. Statistical analysis was performed using a paired t-test, on the collected data, to compare the mean values of the salivary cortisol across the group and within the groups to evaluate the cortisol response to stress. No significant differences were found between the salivary cortisol levels prior to treatment, post oral prophylaxis, or post fluoride treatment at the first and second appointments of both groups. At the first appointment, the fluoride treatment caused a significant increase in the salivary cortisol level over the pretreatment level, in both the groups, but it was not evident in either of the two groups studied at the second appointment. We have concluded that the stress produced by different dental procedures was similar in children from the two groups studied, and the coping ability of the children was also similar in both the groups. Small sample size may be one of the reasons why no significant differences were found between the groups. Similar study needs to be repeated with a larger sample size.


Differential Entropy Preserves Variational Information of Near-Infrared Spectroscopy Time Series Associated With Working Memory.
Neuroscience research shows a growing interest in the application of Near-Infrared Spectroscopy (NIRS) in analysis and decoding of the brain activity of human subjects. Given the correlation that is observed between the Blood Oxygen Dependent Level (BOLD) responses that are exhibited by the time series data of functional Magnetic Resonance Imaging (fMRI) and the hemoglobin oxy/deoxy-genation that is captured by NIRS, linear models play a central role in these applications. This, in turn, results in adaptation of the feature extraction strategies that are well-suited for discretization of data that exhibit a high degree of linearity, namely, slope and the mean as well as their combination, to summarize the informational contents of the NIRS time series. In this article, we demonstrate that these features are inefficient in capturing the variational information of NIRS data, limiting the reliability and the adequacy of the conclusion on their results. Alternatively, we propose the linear estimate of differential entropy of these time series as a natural representation of such information. We provide evidence for our claim through comparative analysis of the application of these features on NIRS data pertinent to several working memory tasks as well as naturalistic conversational stimuli.


A single-molecule long-read survey of the human transcriptome.
Global RNA studies have become central to understanding biological processes, but methods such as microarrays and short-read sequencing are unable to describe an entire RNA molecule from 5' to 3' end. Here we use single-molecule long-read sequencing technology from Pacific Biosciences to sequence the polyadenylated RNA complement of a pooled set of 20 human organs and tissues without the need for fragmentation or amplification. We show that full-length RNA molecules of up to 1.5 kb can readily be monitored with little sequence loss at the 5' ends. For longer RNA molecules more 5' nucleotides are missing, but complete intron structures are often preserved. In total, we identify ∼14,000 spliced GENCODE genes. High-confidence mappings are consistent with GENCODE annotations, but >10% of the alignments represent intron structures that were not previously annotated. As a group, transcripts mapping to unannotated regions have features of long, noncoding RNAs. Our results show the feasibility of deep sequencing full-length RNA from complex eukaryotic transcriptomes on a single-molecule level.


Necessity of radical hysterectomy for endometrial cancer patients with cervical invasion.
To determine whether radical hysterectomy is necessary in the treatment of endometrial cancer patients with cervical involvement, we reviewed the medical records of women who underwent primary surgical treatment for endometrial carcinoma and selected patients with pathologically proven cervical invasion. Among 133 patients, 62 patients underwent extrafascial hysterectomy (EH) and 71 radical or modified radical hysterectomy (RH). The decision regarding EH or RH was made at the discretion of the attending surgeon. The sensitivity of pre-operative magnetic resonance imaging for cervical invasion was 44.7% (38/85). In RH patients, 10/71 (14.1%) patients had frankly histologic parametrial involvement (PMI). All were stage III or over. Eight of 10 patients had pelvic/paraaortic node metastasis and two showed extrauterine spread. In 74 patients with stage II cancer, RH was performed in 41 and PMI was not seen. Sixty-six (89.2%) patients had adjuvant radiation therapy and there were 3 patients who had developed recurrent disease in the RH group and none in the EH group (Mean follow-up: 51 months). Although these findings cannot conclusively refute or support the necessity of radical hysterectomy in patients with cervical extension, it is noteworthy that the risk of PMI seems to be minimal in patients with a tumor confined to the uterus without evidence of extrauterine spread.


An isothermal, label-free, and rapid one-step RNA amplification/detection assay for diagnosis of respiratory viral infections.
Recently, RNA viral infections caused by respiratory viruses, such as influenza, parainfluenza, respiratory syncytial virus, coronavirus, and Middle East respiratory syndrome-coronavirus (MERS-CoV), and Zika virus, are a major public health threats in the world. Although myriads of diagnostic methods based on RNA amplification have been developed in the last decades, they continue to lack speed, sensitivity, and specificity for clinical use. A rapid and accurate diagnostic method is needed for appropriate control, including isolation and treatment of the patients. Here, we report an isothermal, label-free, one-step RNA amplification and detection system, termed as iROAD, for the diagnosis of respiratory diseases. It couples a one-step isothermal RNA amplification method and a bio-optical sensor for simultaneous viral RNA amplification/detection in a label-free and real-time manner. The iROAD assay offers a one-step viral RNA amplification/detection example to rapid analysis (<20min). The detection limit of iROAD assay was found to be 10-times more sensitive than that of real-time reverse transcription-PCR method. We confirmed the clinical utility of the iROAD assay by detecting viral RNAs obtained from 63 human respiratory samples. We envision that the iROAD assay will be useful and potentially adaptable for better diagnosis of emerging infectious diseases including respiratory diseases.


Secukinumab Inhibition of Interleukin-17A in Patients with Psoriatic Arthritis.
In a phase 2 study, the inhibition of the interleukin-17A receptor improved signs and symptoms of psoriatic arthritis. We sought to evaluate the efficacy and safety of secukinumab, an anti-interleukin-17A monoclonal antibody, in such patients. In this double-blind, phase 3 study, 606 patients with psoriatic arthritis were randomly assigned in a 1:1:1 ratio to receive intravenous secukinumab (at a dose of 10 mg per kilogram) at weeks 0, 2, and 4, followed by subcutaneous secukinumab at a dose of either 150 mg or 75 mg every 4 weeks, or placebo. Patients in the placebo group were switched to subcutaneous secukinumab at a dose of 150 mg or 75 mg at week 16 or 24, depending on clinical response. The primary end point was the proportion of patients with an American College of Rheumatology 20 (ACR20) response at week 24, defined as a 20% improvement from baseline in the number of tender and swollen joints and at least three other important domains. ACR20 response rates at week 24 were significantly higher in the group receiving secukinumab at doses of 150 mg (50.0%) and 75 mg (50.5%) than in those receiving placebo (17.3%) (P<0.001 for both comparisons with placebo). Secondary end points, including the ACR50 response and joint structural damage, were significantly better in the secukinumab groups than in the placebo group. Improvements were sustained through 52 weeks. Infections, including candida, were more common in the secukinumab groups. Throughout the study (mean secukinumab exposure, 438.5 days; mean placebo exposure, 128.5 days), four patients in the secukinumab groups had a stroke (0.6 per 100 patient-years; 95% confidence interval [CI], 0.2 to 1.5), and two had a myocardial infarction (0.3 per 100 patient-years; 95% CI, 0.0 to 1.0), as compared with no patients in the placebo group. Secukinumab was more effective than placebo in patients with psoriatic arthritis, which validates interleukin-17A as a therapeutic target. Infections were more common in the secukinumab groups than in the placebo group. The study was neither large enough nor long enough to evaluate uncommon serious adverse events or the risks associated with long-term use. (Funded by Novartis Pharma; ClinicalTrials.gov number, NCT01392326.).


A rapid antimicrobial susceptibility test based on single-cell morphological analysis.
A rapid antibiotic susceptibility test (AST) is desperately needed in clinical settings for fast and appropriate antibiotic administration. Traditional ASTs, which rely on cell culture, are not suitable for urgent cases of bacterial infection and antibiotic resistance owing to their relatively long test times. We describe a novel AST called single-cell morphological analysis (SCMA) that can determine antimicrobial susceptibility by automatically analyzing and categorizing morphological changes in single bacterial cells under various antimicrobial conditions. The SCMA was tested with four Clinical and Laboratory Standards Institute standard bacterial strains and 189 clinical samples, including extended-spectrum β-lactamase-positive Escherichia coli and Klebsiella pneumoniae, imipenem-resistant Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant Enterococci from hospitals. The results were compared with the gold standard broth microdilution test. The SCMA results were obtained in less than 4 hours, with 91.5% categorical agreement and 6.51% minor, 2.56% major, and 1.49% very major discrepancies. Thus, SCMA provides rapid and accurate antimicrobial susceptibility data that satisfy the recommended performance of the U.S. Food and Drug Administration.


Absence of Fas-L aggravates renal injury in acute Trypanosoma cruzi infection.
Trypanosoma cruzi infection induces diverse alterations in immunocompetent cells and organs, myocarditis and congestive heart failure. However, the physiological network of disturbances imposed by the infection has not been addressed thoroughly. Regarding myocarditis induced by the infection, we observed in our previous work that Fas-L-/- mice (gld/gld) have very mild inflammatory infiltration when compared to BALB/c mice. However, all mice from both lineages die in the early acute phase. Therefore, in this work we studied the physiological connection relating arterial pressure, renal function/damage and cardiac insufficiency as causes of death. Our results show that a broader set of dysfunctions that could be classified as a cardio/anaemic/renal syndrome is more likely responsible for cardiac failure and death in both lineages. However, gld/gld mice had very early glomerular deposition of IgM and a more intense renal inflammatory response with reduced renal filtration, which is probably responsible for the premature death in the absence of significant myocarditis in gld/gld.


[Perspectives in the clinical application of pancreas transplantation in the diabetic].
Until June 1983 a total of 280 human pancreatic transplantations had been performed world-wide. Until July 1983, 57 were functioning (22%), 11% for more than 12 months. During the past 5 years a steady increase in the number of segmental transplants has been observed. In most cases simultaneous transplantation of pancreas and kidney was performed (144 cases), in 65 cases the pancreas was transplanted metachronously after kidney grafting, and in 64 cases pancreatic transplantation was performed alone. Currently, segmental or whole pancreatic transplantation is the favoured procedure. Islet transplantation has been disappointing because of the difficulty in procuring sufficient numbers of islets from an adult pancreas followed by immunological destruction of the transplanted islets. Most pancreas grafts have been procured from cadavers, but the favoured segmental technique allows living related donors to be used. After rejection the graft does not always have to be removed and exogenous insulin administration may be resumed, either permanently or until re-transplantation can be accomplished. Life-long immunosuppression is needed after transplantation and currently pancreatic allograft survival rates for cyclosporin (CSA) and azathioprine-treated patients have been similar. The longest survival of a living diabetic recipient with a functioning pancreas is 5 1/2 years. Some authors have recently claimed improvement and stabilization of impaired nerve conduction and diabetic retinopathy after pancreatic transplantation.


Hrd1 and ER-Associated Protein Degradation, ERAD, are Critical Elements of the Adaptive ER Stress Response in Cardiac Myocytes.
Hydroxymethyl glutaryl-coenzyme A reductase degradation protein 1 (Hrd1) is an endoplasmic reticulum (ER)-transmembrane E3 ubiquitin ligase that has been studied in yeast, where it contributes to ER protein quality control by ER-associated degradation (ERAD) of misfolded proteins that accumulate during ER stress. Neither Hrd1 nor ERAD has been studied in the heart, or in cardiac myocytes, where protein quality control is critical for proper heart function. The objective of this study were to elucidate roles for Hrd1 in ER stress, ERAD, and viability in cultured cardiac myocytes and in the mouse heart, in vivo. The effects of small interfering RNA-mediated Hrd1 knockdown were examined in cultured neonatal rat ventricular myocytes. The effects of adeno-associated virus-mediated Hrd1 knockdown and overexpression were examined in the hearts of mice subjected to pressure overload-induced pathological cardiac hypertrophy, which challenges protein-folding capacity. In cardiac myocytes, the ER stressors, thapsigargin and tunicamycin increased ERAD, as well as adaptive ER stress proteins, and minimally affected cell death. However, when Hrd1 was knocked down, thapsigargin and tunicamycin dramatically decreased ERAD, while increasing maladaptive ER stress proteins and cell death. In vivo, Hrd1 knockdown exacerbated cardiac dysfunction and increased apoptosis and cardiac hypertrophy, whereas Hrd1 overexpression preserved cardiac function and decreased apoptosis and attenuated cardiac hypertrophy in the hearts of mice subjected to pressure overload. Hrd1 and ERAD are essential components of the adaptive ER stress response in cardiac myocytes. Hrd1 contributes to preserving heart structure and function in a mouse model of pathological cardiac hypertrophy.


Immunological Techniques to Assess Protein Thiol Redox State: Opportunities, Challenges and Solutions.
To understand oxidative stress, antioxidant defense, and redox signaling in health and disease it is essential to assess protein thiol redox state. Protein thiol redox state is seldom assessed immunologically because of the inability to distinguish reduced and reversibly oxidized thiols by Western blotting. An underappreciated opportunity exists to use Click PEGylation to realize the transformative power of simple, time and cost-efficient immunological techniques. Click PEGylation harnesses selective, bio-orthogonal Click chemistry to separate reduced and reversibly oxidized thiols by selectively ligating a low molecular weight polyethylene glycol moiety to the redox state of interest. The resultant ability to disambiguate reduced and reversibly oxidized species by Western blotting enables Click PEGylation to assess protein thiol redox state. In the present review, to enable investigators to effectively harness immunological techniques to assess protein thiol redox state we critique the chemistry, promise and challenges of Click PEGylation.


Evolving parent-adult child relations: location of multiple children and psychological well-being of older adults in China.
This study examines the interplay among intergenerational emotional closeness, location of multiple children, and parental depressive symptoms in the context of massive migration in rural China. This study is based on a longitudinal survey. Longitudinal data were collected from a stratified random sample of age 60 years and older living in rural townships within Chaohu, a primarily agricultural municipal district with massive out-migration in China. In 2009, 1224 individuals completed the survey, and 977 (79.8% of the original participants) were followed up in 2012. We estimate fixed-effects models to examine how changing collective emotional cohesion and the total composition of children's location affect parents' depressive symptoms. Descriptive analyses show that both the composition of children's location and intergenerational emotional closeness are subject to changes during a 3-year survey interval. Results from fixed-effect models further demonstrate that collective emotional closeness and psychological well-being are positively associated with each other. This association is the strongest when all children are local, but it becomes less prominent when there are more migrant than local children. This study has provided important evidence that both intergenerational cohesion and location of multiple children evolve over time and jointly influence parents' psychological well-being in later life. The left-behind older adults are not necessarily the most vulnerable group in rural China. Those with most adult children living close by could also suffer from a deficit in psychological well-being if the emotional bond between them is weak.


MicroRNA expression differences in human hematopoietic cell lineages enable regulated transgene expression.
Blood microRNA (miRNA) levels have been associated with and shown to participate in disease pathophysiology. However, the hematopoietic cell of origin of blood miRNAs and the individual blood cell miRNA profiles are poorly understood. We report the miRNA content of highly purified normal hematopoietic cells from the same individuals. Although T-cells, B-cells and granulocytes had the highest miRNA content per cell, erythrocytes contributed more cellular miRNA to the blood, followed by granulocytes and platelets. miRNA profiling revealed different patterns and different expression levels of miRNA specific for each lineage. miR-30c-5p was determined to be an appropriate reference normalizer for cross-cell qRT-PCR comparisons. miRNA profiling of 5 hematopoietic cell lines revealed differential expression of miR-125a-5p. We demonstrated endogenous levels of miR-125a-5p regulate reporter gene expression in Meg-01 and Jurkat cells by (1) constructs containing binding sites for miR-125a-5p or (2) over-expressing or inhibiting miR-125a-5p. This quantitative analysis of the miRNA profiles of peripheral blood cells identifies the circulating hematopoietic cellular miRNAs, supports the use of miRNA profiles for distinguishing different hematopoietic lineages and suggests that endogenously expressed miRNAs can be exploited to regulate transgene expression in a cell-specific manner.


Surface expression and subunit specific control of steady protein levels by the Kv7.2 helix A-B linker.
Kv7.2 and Kv7.3 are the main components of the neuronal voltage-dependent M-current, which is a subthreshold potassium conductance that exerts an important control on neuronal excitability. Despite their predominantly intracellular distribution, these channels must reach the plasma membrane in order to control neuronal activity. Thus, we analyzed the amino acid sequence of Kv7.2 to identify intrinsic signals that may control its surface expression. Removal of the interlinker connecting helix A and helix B of the intracellular C-terminus produces a large increase in the number of functional channels at the plasma membrane. Moreover, elimination of this linker increased the steady-state amount of protein, which was not associated with a decrease of protein degradation. The magnitude of this increase was inversely correlated with the number of helix A - helix B linkers present in the tetrameric channel assemblies. In contrast to the remarkable effect on the amount of Kv7.2 protein, removal of the Kv7.2 linker had no detectable impact on the steady-state levels of Kv7.3 protein.


Single nucleotide polymorphism in the RAD18 gene and risk of colorectal cancer in the Japanese population.
The RAD18 gene, located on the human chromosome 3p24-p25, plays a crucial role in post-replication repair (PRR) in various organisms from yeast to humans. In the human RAD18 gene, one coding single nucleotide polymorphism (SNP) at codon 302, encoding either arginine (Arg, CGA) or glutamine (Gln, CAA), was reported. Although the molecular function of the RAD18 protein came to be elucidated, the association between the RAD18 Arg302Gln polymorphism and the risk of human cancer development was not examined. Therefore, we investigated the relationship between the polymorphism and the development of human primary colorectal cancer (CRC). The Arg302Gln polymorphism in 100 patients with CRC and 200 healthy controls were genotyped by the polymerase chain reaction with confronting two-pair primer (PCR-CTPP) assay. The Gln/Gln genotype was significantly more frequent in CRC (18.0%) than in the healthy controls (11.5%) (p=0.046). The increased risk was detected in CRC patients with the Gln/Gln genotype (Odds ratio [OR], 2.10; 95% confidence interval [CI], 1.00 to 4.40). When the relationship of the SNP with clinicopathological parameters of CRC was investigated, particularly in the well-differentiated grade and in the lymph node metastasis (N1) CRC patients, significantly higher risks were detected (OR, 7.00; 95% CI, 1.19-41.1 and OR, 3.71; 95% CI, 1.30-10.6, respectively). These results suggested that the RAD18 Arg302Gln polymorphism is associated with the risk of CRC. This report provides evidence for an association between the RAD18 Arg302Gln polymorphism and human CRC risk.


Clinical research evidence of cupping therapy in China: a systematic literature review.
Though cupping therapy has been used in China for thousands of years, there has been no systematic summary of clinical research on it.This review is to evaluate the therapeutic effect of cupping therapy using evidence-based approach based on all available clinical studies. We included all clinical studies on cupping therapy for all kinds of diseases. We searched six electronic databases, all searches ended in December 2008. We extracted data on the type of cupping and type of diseases treated. 550 clinical studies were identified published between 1959 and 2008, including 73 randomized controlled trials (RCTs), 22 clinical controlled trials, 373 case series, and 82 case reports. Number of RCTs obviously increased during past decades, but the quality of the RCTs was generally poor according to the risk of bias of the Cochrane standard for important outcome within each trials. The diseases in which cupping was commonly employed included pain conditions, herpes zoster, cough or asthma, etc. Wet cupping was used in majority studies, followed by retained cupping, moving cupping, medicinal cupping, etc. 38 studies used combination of two types of cupping therapies. No serious adverse effects were reported in the studies. According to the above results, quality and quantity of RCTs on cupping therapy appears to be improved during the past 50 years in China, and majority of studies show potential benefit on pain conditions, herpes zoster and other diseases. However, further rigorous designed trials in relevant conditions are warranted to support their use in practice.


Long-lasting immunogenicity of a virosomal vaccine in older children and young adults with type I diabetes mellitus.
To evaluate the long-lasting immunogenicity and reactogenicity of a virosomal influenza vaccine in subjects with type I diabetes, a trial was conducted during the 2007-2008 influenza season in Milan, Northern Italy. One hundred five subjects aged 9-30 years were randomized to receive by intramuscular injection vaccination by a single dose (0.5 ml) of either a virosomal (Inflexal V) (n=52) or a standard subunit (Influvac) (n=53) vaccine. Serum hemagglutinin inhibition antibody titres were determined against the three recommended influenza-like strains, A/H1N1, A/H3N2 and B, at pre-vaccination, and 1 and 6 months post-vaccination. Geometric mean titres were increased in the two groups 1 and 6 months post-vaccination (P<0.001). One month post-vaccination both vaccines met the CPMP requirement for immunogenicity with high seroprotection rates (>95%) for strains A/H1N1 and A/H3N2, and a seroprotection of 73% and 70% in the virosomal and subunit vaccine for strain B. Mean fold increase ranged 2.8 (A/H3N2)-6.2 (A/H1N1) in the virosomal group and 2.3 (A/H3N2)-4.8 (A/H1N1) in the subunit group. Immunogenicity declined 6 months post-vaccination in both groups, and the CPMP requirement for immunogenicity was satisfied only in the virosomal group. In subjects without pre-existing antibodies to strain B (titre <10), the virosomal vaccine showed higher immune response than the subunit vaccine 6 months post-vaccination, with a geometric mean titre (95% CI) of 40.2 (30.7-54.6) vs. 21.2 (14.6-30.8). Reactogenicity was similar in the two vaccines. All reactions were transient and not severe. The results indicate that in older children and young adults with type I diabetes influenza vaccination with a virosomal or a standard subunit vaccine is safe and adequately immunogenic against the three influenza vaccine strains. In addition, the virosomal vaccine may show better long-lasting immune response than the standard subunit vaccine, especially in subjects without pre-existing antibodies to influenza strains.


Medicine. Consent from donors for embryo and stem cell research.
As research with human embryos and embryonic stem cells proceeds, the authors of this Policy Forum argue that all donors of biological materials should give informed consent, including oocyte and sperm donors. Informed consent is particularly important because of the diverse opinions and strong emotions that surround such research. Some gamete donors who are willing to help women and couples bear children may object to the use of their genetic materials for certain types of research.


Determinants of malnutrition among urban slum children in Bangladesh.
This paper analyzes the role of child, maternal and household variables on weight-for-age nutritional status of children in the largest urban slum of Bangladesh. We use anthropometric weight-for-age nutrition status of children for an ordered logistic analysis. Our dataset gives us the advantage of segregating health knowledge into three indices: health-seeking practices index, child health precautions index and medical cost knowledge index, which are used as covariates to understand the role of health knowledge towards child health. Gender specific regressions are also run to understand male and female children nutritional function differences. Per capita income significantly improves child health but household assets do not, casting doubt on the robustness of permanent income. After controlling for health knowledge and health-seeking behavior, the remaining impact of maternal education on child health is no longer significant. Health knowledge indices significantly improve child health albeit differentially. While male children are more sensitive to "child health precautions" and "medical cost knowledge", female children are more sensitive to "health-seeking practices". Role of health knowledge on child health carries a significant portion of the education effect. Policy makers looking to improve the nutritional status of female children vis-a-vis male children in study area, should promote programs focusing on health-seeking practices.


Anti-inflammatory Activity of Berry Fruits in Mice Model of Inflammation is Based on Oxidative Stress Modulation.
Many fruits have been used as nutraceuticals because the presence of bioactive molecules that play biological activities. The present study was designed to compare the anti-inflammatory and antioxidant effects of methanolic extracts of Lycium barbarum (GOJI), Vaccinium macrocarpon (CRAN) and Vaccinium myrtillus (BLUE). Mices were treated with extracts (50 and 200 mg/kg, p.o.), twice a day through 10 days. Phytochemical analysis was performed by high-performance liquid chromatography. Antioxidant activity was determine by 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, reducing power, lipid peroxidation thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) and catalase (CAT) activity. Anti-inflammatory activity was evaluated by paw edema followed by determination of myeloperoxidase (MPO) and TBARS. High amount of phenolic compounds, including rutin, were identified in all berries extracts. However, quercetin was observed only in BLUE and CRAN. GOJI presents higher scavenging activity of DPPH radical and reducing power than BLUE and CRAN. The extracts improved antioxidant status in liver; BLUE showed the largest reduction (75.3%) in TBARS when compared to CRAN (70.7%) and GOJI (65.3%). Nonetheless, CAT activity was lower in BLUE group. However, hepatic concentrations of GSH were higher in animals treated with GOJI rather than CRAN and BLUE. Despite all fruits caused a remarkable reduction in paw edema and TBARS, only BLUE and CRAN were able to reduce MPO. These results suggest that quercetin, rutin, or other phenolic compound found in these berry fruits extracts could produce an anti-inflammatory response based on modulation of oxidative stress in paw edema model. Within fruits broadly consumed because of its nutraceuticals properties include, Lycium barbarum (Goji berry), Vaccinium myrtillus (Blueberry or Bilberry) and Vaccinium macrocarpon (Cranberry)The objectives of this study were the investigation and comparison of chemical composition, antioxidant activity "in vitro" and "in vivo" and anti inflammatory property of berry fruits bought dry form.In summary, two main findings can be addressed with this study: (1) Berry fruits presented antioxidant and anti inflammatory activities "in vitro" and "in vivo"; (2) the extracts of GOJI, CRAN, and BLUE modulate the inflammatory process by different mechanisms.


Molecular genetics of syndromic and non-syndromic forms of parathyroid carcinoma.
Parathyroid carcinoma (PC) may occur as part of a complex hereditary syndrome or an isolated (i.e., non-syndromic) non-hereditary (i.e., sporadic) endocrinopathy. Studies of hereditary and syndromic forms of PC, which include the hyperparathyroidism-jaw tumor syndrome (HPT-JT), multiple endocrine neoplasia types 1 and 2 (MEN1 and MEN2), and familial isolated primary hyperparathyroidism (FIHP), have revealed some genetic mechanisms underlying PC. Thus, cell division cycle 73 (CDC73) germline mutations cause HPT-JT, and CDC73 mutations occur in 70% of sporadic PC, but in only ∼2% of parathyroid adenomas. Moreover, CDC73 germline mutations occur in 20%-40% of patients with sporadic PC and may reveal unrecognized HPT-JT. This indicates that CDC73 mutations are major driver mutations in the etiology of PCs. However, there is no genotype-phenotype correlation and some CDC73 mutations (e.g., c.679_680insAG) have been reported in patients with sporadic PC, HPT-JT, or FIHP. Other genes involved in sporadic PC include germline MEN1 and rearranged during transfection (RET) mutations and somatic alterations of the retinoblastoma 1 (RB1) and tumor protein P53 (TP53) genes, as well as epigenetic modifications including DNA methylation and histone modifications, and microRNA misregulation. This review summarizes the genetics and epigenetics of the familial syndromic and non-syndromic (sporadic) forms of PC.


Judging a protein by more than its name: GSK-3.
As knowledge of cellular signal transduction has accumulated, general truisms have emerged, including the notion that signaling proteins are usually activated by stimuli and that they, in turn, mediate the actions of specific agonists. Glycogen synthase kinase-3 (GSK-3) is an unusual protein-serine kinase that bucks these conventions. This evolutionarily conserved protein kinase is active in resting cells and is inhibited in response to activation of several distinct pathways, including those acting by elevation of 3' phosphorylated phosphatidylinositol lipids and adenosine 3'-5'-monophosphate (cAMP). In addition, GSK-3 is distinctly regulated by, and is a core component of, the Wnt pathway. This review describes the unique characteristics of this decidedly oddball protein kinase in terms of its diverse biological functions, plethora of targets, role in several human diseases, and consequential potential as a therapeutic target.


Social, state-dependent and environmental modulation of faecal corticosteroid levels in free-ranging female spotted hyenas.
Little is known about to what extent the sensitivity of the hypothalamic-pituitary-adrenal (HPA) axis may be state dependent and vary in the same species between environments. Here we tested whether the faecal corticosteroid concentrations of matrilineal adult female spotted hyenas are influenced by social and reproductive status in adjacent ecosystems and whether they vary between periods with and without social stress. Females in the Serengeti National Park frequently become socially subordinate intruders in other hyena territories by undertaking long-distance foraging trips to migratory herds, whereas in the Ngorongoro Crater they usually forage inside their own small territories on resident prey. The faecal corticosteroid concentrations in Serengeti females were significantly higher than in Ngorongoro females. Energy expenditure by lactation is exceptionally high in spotted hyenas and this may be reflected in their corticosteroid levels. The faecal corticosteroid levels in both populations were higher in lactating than in non-lactating females. During periods of social stability, faecal corticosteroid concentrations increased in non-lactating females but not in lactating females as social status declined. Lactating Serengeti females had significantly higher faecal corticosteroid concentrations during periods with acute severe social stress than during periods without, indicating that the HPA axis is sensitive to social stimuli even in lactating females. So far few studies have used non-invasive monitoring methods for assessing social stress in freeranging animals. This study demonstrates for the first time, to the authors' knowledge, that corticosteroid concentrations may differ between periods with and without social stress for a free-ranging female mammal and that the modulating effect of social status may depend on reproductive status.


The Bisphenol A Induced Oxidative Stress in Non-Alcoholic Fatty Liver Disease Male Patients: A Clinical Strategy to Antagonize the Progression of the Disease.
:Introduction: Bisphenol A (BPA) exposure has been correlated to non-alcoholic fatty liver disease (NAFLD) development and progression. We investigated, in a clinical model, the effects of the administration of 303 mg of silybin phospholipids complex, 10 g of vitamin D, and 15 mg of vitamin E (RealSIL, 100D, IBI-Lorenzini, Aprilia, Italy) in male NAFLD patients exposed to BPA on metabolic, hormonal, and oxidative stress-related parameters. We enrolled 32 male patients with histologic diagnosis of NAFLD and treated them with Realsil 100D twice a day for six months. We performed at baseline clinical, biochemical, and food consumption assessments as well as the evaluation of physical exercise, thiobarbituric acid reactive substances (TBARS), plasmatic and urinary BPA and estrogen levels. The results obtained were compared with those of healthy control subjects and, in the NAFLD group, between baseline and the end of treatment. A direct proportionality between TBARS levels and BPA exposure was shown (p < 0.0001). The therapy determined a reduction of TBARS levels (p = 0.011), an improvement of alanine aminotransferase, aspartate aminotransferase, insulinemia, homeostatic model assessment insulin resistance, C reactive protein, tumor necrosis factor alpha (p < 0.05), an increase of conjugated BPA urine amount, and a reduction of its free form (p < 0.0001; p = 0.0002). Moreover, the therapy caused an increase of plasmatic levels of the native form of estrogens (p = 0.03). We highlighted the potential role of BPA in estrogen oxidation and oxidative stress in NAFLD patients. The use of Realsil 100D could contribute to fast BPA detoxification and to improve cellular antioxidant power, defending the integrity of biological estrogen-dependent pathways.


Multi-institutional experience of stereotactic body radiotherapy for large (≥5 centimeters) non-small cell lung tumors.
Stereotactic body radiotherapy (SBRT) is the standard of care for patients with nonoperative, early-stage non-small cell lung cancer (NSCLC) measuring < 5 cm, but its use among patients with tumors measuring ≥5 cm is considerably less defined, with the existing literature limited to small, single-institution reports. The current multi-institutional study reported outcomes evaluating the largest such population reported to date. Clinical/treatment characteristics, outcomes, toxicities, and patterns of failure were assessed in patients with primary NSCLC measuring ≥5 cm without evidence of distant/lymph node metastasis who underwent SBRT using ≤5 fractions. Statistics included Kaplan-Meier survival analyses and univariate/multivariate Cox proportional hazards models. A total of 92 patients treated from 2004 through 2016 were analyzed from 12 institutions. The median follow-up was 12 months (15 months in survivors). The median age and tumor size among the patients were 73 years (range, 50-95 years) and 5.4 cm (range, 5.0-7.5 cm), respectively. The median dose/fractionation was 50 Gray/5 fractions. The actuarial local control rates at 1 year and 2 years were 95.7% and 73.2%, respectively. The disease-free survival rate was 72.1% and 53.5%, respectively, at 1 year and 2 years. The 1-year and 2-year disease-specific survival rates were 95.5% and 78.6%, respectively. The median, 1-year, and 2-year overall survival rates were 21.4 months, 76.2%, and 46.4%, respectively. On multivariate analysis, lung cancer history and pre-SBRT positron emission tomography maximum standardized uptake value were found to be associated with overall survival. Posttreatment failures were most commonly distant (33% of all disease recurrences), followed by local (26%) and those occurring elsewhere in the lung (23%). Three patients had isolated local failures. Grade 3 to 4 toxicities included 1 case (1%) and 4 cases (4%) of grade 3 dermatitis and radiation pneumonitis, respectively (toxicities were graded according to the Common Terminology Criteria for Adverse Events [version 4.0]). Grades 2 to 5 radiation pneumonitis occurred in 11% of patients. One patient with a tumor measuring 7.5 cm and a smoking history of 150 pack-years died of radiation pneumonitis. The results of the current study, which is the largest study of patients with NSCLC measuring ≥5 cm reported to date, indicate that SBRT is a safe and efficacious option. Cancer 2017;123:688-696. © 2016 American Cancer Society.


Salivary gland tumors: A 20-year review of clinical diagnostic accuracy at a single center.
Obtaining reliable pre-operative diagnosis is crucial in planning treatment for patients with salivary gland tumors. The purpose of this study was to evaluate the accuracy of pre-operative clinical diagnosis of salivary gland tumors managed at a single tertiary university hospital over a period of 20 years. A retrospective analysis of the period between 1992 and 2011 was carried out to review the cases of patients with salivary gland tumors. A total of 101 patients were enrolled and general data were described. Clinical diagnosis was compared with the final pathological diagnosis to reveal the clinical diagnostic accuracy. Of the parotid and submandibular gland tumors, 86 and 67% were benign, respectively. The clinical diagnostic accuracies for diagnosis of parotid tumors as benign or malignant were 100 and 57%, respectively. The clinical diagnostic accuracies for diagnosis of submandibular tumors as benign or malignant were 67%. Therefore, the overall clinical judgment of benign and malignant tumors in the submandibular gland is unreliable. The accuracy for a parotid tumor to be clinically interpreted as benign was 100%. While it is difficult to draw any conclusion for non-parotid gland tumors, surgical intervention should be recommended in patients with parotid tumors clinically suspected to be malignant, and all submandibular, sublingual and minor salivary gland tumors.


Heart rate monitoring: applications and limitations.
Over the last 20 years, heart rate monitors (HRMs) have become a widely used training aid for a variety of sports. The development of new HRMs has also evolved rapidly during the last two decades. In addition to heart rate (HR) responses to exercise, research has recently focused more on heart rate variability (HRV). Increased HRV has been associated with lower mortality rate and is affected by both age and sex. During graded exercise, the majority of studies show that HRV decreases progressively up to moderate intensities, after which it stabilises. There is abundant evidence from cross-sectional studies that trained individuals have higher HRV than untrained individuals. The results from longitudinal studies are equivocal, with some showing increased HRV after training but an equal number of studies showing no differences. The duration of the training programmes might be one of the factors responsible for the versatility of the results.HRMs are mainly used to determine the exercise intensity of a training session or race. Compared with other indications of exercise intensity, HR is easy to monitor, is relatively cheap and can be used in most situations. In addition, HR and HRV could potentially play a role in the prevention and detection of overtraining. The effects of overreaching on submaximal HR are controversial, with some studies showing decreased rates and others no difference. Maximal HR appears to be decreased in almost all 'overreaching' studies. So far, only few studies have investigated HRV changes after a period of intensified training and no firm conclusions can be drawn from these results. The relationship between HR and oxygen uptake (VO(2)) has been used to predict maximal oxygen uptake (VO(2max)). This method relies upon several assumptions and it has been shown that the results can deviate up to 20% from the true value. The HR-VO(2) relationship is also used to estimate energy expenditure during field conditions. There appears to be general consensus that this method provides a satisfactory estimate of energy expenditure on a group level, but is not very accurate for individual estimations. The relationship between HR and other parameters used to predict and monitor an individual's training status can be influenced by numerous factors. There appears to be a small day-to-day variability in HR and a steady increase during exercise has been observed in most studies. Furthermore, factors such as dehydration and ambient temperature can have a profound effect on the HR-VO(2) relationship.


Custom microarray for glycobiologists: considerations for glycosyltransferase gene expression profiling.
The development of microarray technology offers the unprecedented possibility of studying the expression of thousands of genes in one experiment. Its exploitation in the glycobiology field will eventually allow the parallel investigation of the expression of many glycosyltransferases, which will ultimately lead to an understanding of the regulation of glycoconjugate synthesis. While numerous gene arrays are available on the market, e.g. the Affymetrix GeneChip arrays, glycosyltransferases are not adequately represented, which makes comprehensive surveys of their gene expression difficult. This chapter describes the main issues related to the establishment of a custom glycogenes array.


Remobilization of Old Permafrost Carbon to Chukchi Sea Sediments During the End of the Last Deglaciation.
Climate warming is expected to destabilize permafrost carbon (PF-C) by thaw-erosion and deepening of the seasonally thawed active layer and thereby promote PF-C mineralization to CO2 and CH4. A similar PF-C remobilization might have contributed to the increase in atmospheric CO2 during deglacial warming after the last glacial maximum. Using carbon isotopes and terrestrial biomarkers (Δ14C, δ13C, and lignin phenols), this study quantifies deposition of terrestrial carbon originating from permafrost in sediments from the Chukchi Sea (core SWERUS-L2-4-PC1). The sediment core reconstructs remobilization of permafrost carbon during the late Allerød warm period starting at 13,000 cal years before present (BP), the Younger Dryas, and the early Holocene warming until 11,000 cal years BP and compares this period with the late Holocene, from 3,650 years BP until present. Dual-carbon-isotope-based source apportionment demonstrates that Ice Complex Deposit-ice- and carbon-rich permafrost from the late Pleistocene (also referred to as Yedoma)-was the dominant source of organic carbon (66 ± 8%; mean ± standard deviation) to sediments during the end of the deglaciation, with fluxes more than twice as high (8.0 ± 4.6 g·m-2·year-1) as in the late Holocene (3.1 ± 1.0 g·m-2·year-1). These results are consistent with late deglacial PF-C remobilization observed in a Laptev Sea record, yet in contrast with PF-C sources, which at that location were dominated by active layer material from the Lena River watershed. Release of dormant PF-C from erosion of coastal permafrost during the end of the last deglaciation indicates vulnerability of Ice Complex Deposit in response to future warming and sea level changes.


Contrasting effects of finger and shoulder interpersonal light touch on standing balance.
Sway is reduced by light nonsupporting touch between parts of the body and a fixed surface. This effect is assumed to reflect augmentation of sensory cues for sway by point-of-contact reaction forces. It has been shown that movement of the contact surface can increase sway relative to an earth-fixed contact. Light touch contact with another person, for example, holding hands, affords a moving contact due to partner sway. We asked whether interpersonal light touch (IPLT) would increase sway relative to standing alone. We expected effects on sway to vary as a function of the site of contact and the postural stability of each partner. Eight pairs of participants, standing in either normal bipedal or tandem Romberg stance with eyes closed and using IPLT (finger to finger or shoulder to shoulder) or no contact, provided 4 trials of 30-s duration in each of 12 posture-touch combinations. Sway (SD of the rate of change of upper trunk position at C7) was reliably less with IPLT compared with no contact, with two exceptions: in normal stance, shoulder contact with a partner in tandem stance, and in tandem Romberg stance, finger contact with a partner in the same stance, increased sway. Otherwise, the reduction in sway was greater with shoulder than with finger contact. Measures of interpersonal synchronization based on cross-correlations and coherence analysis between the partners' C7 movements suggest different control factors operate to reduce sway in IPLT with the hand or shoulder contact.


Manual therapy compared with physical therapy in patients with non-specific neck pain: a randomized controlled trial.
Manual therapy according to the School of Manual Therapy Utrecht (MTU) is a specific type of passive manual joint mobilization. MTU has not yet been systematically compared to other manual therapies and physical therapy. In this study the effectiveness of MTU is compared to physical therapy, particularly active exercise therapy (PT) in patients with non-specific neck pain. Patients neck pain, aged between 18-70 years, were included in a pragmatic randomized controlled trial with a one-year follow-up. Primary outcome measures were global perceived effect and functioning (Neck Disability Index), the secondary outcome was pain intensity (Numeric Rating Scale for Pain). Outcomes were measured at 3, 7, 13, 26 and 52 weeks. Multilevel analyses (intention-to-treat) were the primary analyses for overall between-group differences. Additional to the primary and secondary outcomes the number of treatment sessions of the MTU group and PT group was analyzed. Data were collected from September 2008 to February 2011. A total of 181 patients were included. Multilevel analyses showed no statistically significant overall differences at one year between the MTU and PT groups on any of the primary and secondary outcomes. The MTU group showed significantly lower treatment sessions compared to the PT group (respectively 3.1 vs. 5.9 after 7 weeks; 6.1 vs. 10.0 after 52 weeks). Patients with neck pain improved in both groups without statistical significantly or clinically relevant differences between the MTU and PT groups during one-year follow-up. ClinicalTrials.gov Identifier: NCT00713843.


High-throughput screening identifies suppressors of mitochondrial fragmentation in OPA1 fibroblasts.
Mutations in OPA1 cause autosomal dominant optic atrophy (DOA) as well as DOA+, a phenotype characterized by more severe neurological deficits. OPA1 deficiency causes mitochondrial fragmentation and also disrupts cristae, respiration, mitochondrial DNA (mtDNA) maintenance, and cell viability. It has not yet been established whether phenotypic severity can be modulated by genetic modifiers of OPA1. We screened the entire known mitochondrial proteome (1,531 genes) to identify genes that control mitochondrial morphology using a first-in-kind imaging pipeline. We identified 145 known and novel candidate genes whose depletion promoted elongation or fragmentation of the mitochondrial network in control fibroblasts and 91 in DOA+ patient fibroblasts that prevented mitochondrial fragmentation, including phosphatidyl glycerophosphate synthase (PGS1). PGS1 depletion reduces CL content in mitochondria and rebalances mitochondrial dynamics in OPA1-deficient fibroblasts by inhibiting mitochondrial fission, which improves defective respiration, but does not rescue mtDNA depletion, cristae dysmorphology, or apoptotic sensitivity. Our data reveal that the multifaceted roles of OPA1 in mitochondria can be functionally uncoupled by modulating mitochondrial lipid metabolism, providing novel insights into the cellular relevance of mitochondrial fragmentation.